SARS-CoV-2 polyprotein substrate regulates the stepwise Mpro cleavage reaction.

The processing of the Coronavirus polyproteins pp1a and pp1ab by the main protease Mpro to produce mature proteins is a crucial event in virus replication and a promising target for antiviral drug development. Mpro cleaves polyproteins in a defined order, but how Mpro and/or the polyproteins determine the order of cleavage remains enigmatic due to a lack of structural information about polyprotein-bound Mpro. Here, we present the cryo-EM structures of SARS-CoV-2 Mpro in an apo form and in complex with the nsp7-10 region of the pp1a polyprotein. The complex structure shows that Mpro interacts with only the recognition site residues between nsp9 and nsp10, without any association with the rest of the polyprotein. Comparison between the apo form and polyprotein-bound structures of Mpro highlights the flexible nature of the active site region of Mpro, which allows it to accommodate ten recognition sites found in the polyprotein. These observations suggest that the role of Mpro in selecting a preferred cleavage site is limited and underscores the roles of the structure, conformation, and/or dynamics of the polyproteins in determining the sequence of polyprotein cleavage by Mpro.

SARS-CoV-2 replication and drug discovery.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to wreak havoc across the globe. This sudden and deadly pandemic emphasizes the necessity for anti-viral drug development that can be rapidly administered to reduce morbidity, mortality, and virus propagation. Thus, lacking efficient anti-COVID-19 treatment, and especially given the lengthy drug development process as well as the critical death tool that has been associated with SARS-CoV-2 since its outbreak, drug repurposing (or repositioning) constitutes so far, the ideal and ready-to-go best approach in mitigating viral spread, containing the infection, and reducing the COVID-19-associated death rate. Indeed, based on the molecular similarity approach of SARS-CoV-2 with previous coronaviruses (CoVs), repurposed drugs have been reported to hamper SARS-CoV-2 replication. Therefore, understanding the inhibition mechanisms of viral replication by repurposed anti-viral drugs and chemicals known to block CoV and SARS-CoV-2 multiplication is crucial, and it opens the way for particular treatment options and COVID-19 therapeutics. In this review, we highlighted molecular basics underlying drug-repurposing strategies against SARS-CoV-2. Notably, we discussed inhibition mechanisms of viral replication, involving and including inhibition of SARS-CoV-2 proteases (3C-like protease, 3CLpro or Papain-like protease, PLpro) by protease inhibitors such as Carmofur, Ebselen, and GRL017, polymerases (RNA-dependent RNA-polymerase, RdRp) by drugs like Suramin, Remdesivir, or Favipiravir, and proteins/peptides inhibiting virus-cell fusion and host cell replication pathways, such as Disulfiram, GC376, and Molnupiravir. When applicable, comparisons with SARS-CoV inhibitors approved for clinical use were made to provide further insights to understand molecular basics in inhibiting SARS-CoV-2 replication and draw conclusions for future drug discovery research.

Development of potent and effective SARS-CoV-2 main protease inhibitors based on maleimide analogs for the potential treatment of COVID-19.

In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, 6e demonstrated the highest activity in the enzymatic assay with an IC50 value of 8.52 ± 0.44 µM. The IC50 value for Nirmatrelvir (PF-07321332, used as a reference) was 0.84 ± 0.37 µM. The cytotoxic properties were determined in the MTT assay using MRC-5 and HEK-293 cell lines. In the course of the investigation, we found that the newly obtained maleimide derivatives are not substantially cytotoxic (IC50 values for most compounds were above 200 µM).

Macrophage Activation Syndrome in Coinciding Pandemics of Obesity and COVID-19: Worse than Bad.

Epigenetic changes have long-lasting impacts, which influence the epigenome and are maintained during cell division. Thus, human genome changes have required a very long timescale to become a major contributor to the current obesity pandemic. Whereas bidirectional effects of coronavirus disease 2019 (COVID-19) and obesity pandemics have given the opportunity to explore, how the viral microribonucleic acids (miRNAs) use the human's transcriptional machinery that regulate gene expression at a posttranscriptional level. Obesity and its related comorbidity, type 2 diabetes (T2D), and new-onset diabetes due to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are additional risk factors, which increase the severity of COVID-19 and its related mortality. The higher mortality rate of these patients is dependent on severe cytokine storm, which is the sum of the additional cytokine production by concomitant comorbidities and own cytokine synthesis of COVID-19. Patients with obesity facilitate the SARS-CoV-2 entry to host cell via increasing the host's cell receptor expression and modifying the host cell proteases. After entering the host cells, the SARS-CoV-2 genome directly functions as a messenger ribonucleic acid (mRNA) and encodes a set of nonstructural proteins via processing by the own proteases, main protease (Mpro), and papain-like protease (PLpro) to initiate viral genome replication and transcription. Following viral invasion, SARS-CoV-2 infection reduces insulin secretion via either inducing ß-cell apoptosis or reducing intensity of angiotensin-converting enzyme 2 (ACE2) receptors and leads to new-onset diabetes. Since both T2D and severity of COVID-19 are associated with the increased serum levels of pro-inflammatory cytokines, high glucose levels in T2D aggravate SARS-CoV-2 infection. Elevated neopterin (NPT) value due to persistent interferon gamma (IFN-γ)-mediated monocyte-macrophage activation is an indicator of hyperactivated pro-inflammatory phenotype M1 macrophages. Thus, NPT could be a reliable biomarker for the simultaneously occurring COVID-19-, obesity- and T2D-induced cytokine storm. While host miRNAs attack viral RNAs, viral miRNAs target host transcripts. Eventually, the expression rate and type of miRNAs also are different in COVID-19 patients with different viral loads. It is concluded that specific miRNA signatures in macrophage activation phase may provide an opportunity to become aware of the severity of COVID-19 in patients with obesity and obesity-related T2D.

Improved SARS-CoV-2 main protease high-throughput screening assay using a 5-carboxyfluorescein substrate.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global threat to human health has highlighted the need for the development of novel therapies targeting current and emerging coronaviruses with pandemic potential. The coronavirus main protease (Mpro, also called 3CLpro) is a validated drug target against coronaviruses and has been heavily studied since the emergence of SARS-CoV-2 in late 2019. Here, we report the biophysical and enzymatic characterization of native Mpro, then characterize the steady-state kinetics of several commonly used FRET substrates, fluorogenic substrates, and six of the 11 reported SARS-CoV-2 polyprotein cleavage sequences. We then assessed the suitability of these substrates for high-throughput screening. Guided by our assessment of these substrates, we developed an improved 5-carboxyfluorescein-based FRET substrate, which is better suited for high-throughput screening and is less susceptible to interference and false positives than existing substrates. This study provides a useful framework for the design of coronavirus Mpro enzyme assays to facilitate the discovery and development of therapies targeting Mpro.

Investigating theobromine as a potential anti-human coronaviral agent.

Coronaviruses (CoVs) have long been known to infect humans, mainly alpha-CoV and beta-CoV. The vaccines developed for SARS-CoV-2 are likely not effective against other coronavirus species, whereas the risk of the emergence of new strains that may cause the next epidemic/pandemic is high. The development of antiviral drugs that are effective across different CoVs represents a viable strategy for improving pandemic preparedness. In this study, we aim to identify pan-coronaviral agents by targeting the conserved main protease (Mpro). For drug screening, the catalytic dyad of four human CoVs (HCoVs: SARS-CoV-2, and seasonal CoV NL63, OC43, and 229E) was targeted by molecular docking. The identified leading candidate theobromine, a xanthine derivative, was further tested in cell culture models of coronavirus infection. Theobromine binds strongly with the catalytic dyad (His41 and Cys144/145) of SARS-CoV-2 and HCoV-NL63 Mpro, mildly with HCoV-OC43, but not with HCoV-229E. However, theobromine only shows dose-dependent inhibition in Calu3 cells inoculated with SARS-CoV-2, but not in cells inoculated with seasonal CoVs. Theobromine exerts antiviral activity against coronavirus infections potentially through targeting Mpro. However, the antiviral potency is distinct among different CoVs.

Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3-d]pyrimidines as potential active site inhibitors and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro.

In this paper, an environmentally benign, convenient, and efficient one-pot three-component reaction has been developed for the regioselective synthesis of novel 5-aroyl(or heteroaroyl)-6-(alkylamino)-1,3-dimethylfuro[2,3-d]pyrimidine-2,4(1H,3H)-diones (4a‒n) through the sequential condensation of aryl(or heteroaryl)glyoxal monohydrates (1a‒g), 1,3-dimethylbarbituric acid (2), and alkyl(viz. cyclohexyl or tert-butyl)isocyanides (3a or 3b) catalyzed by ultra-low loading ZrOCl2•8H2O (just 2 mol%) in water at 50 ˚C. After synthesis and characterization of the mentioned furo[2,3-d]pyrimidines (4a‒n), their multi-targeting inhibitory properties were investigated against the active site and putative allosteric hotspots of both SARS-CoV-2 main protease (MPro) and papain-like protease (PLPro) based on molecular docking studies and compare the attained results with various medicinal compounds which approximately in three past years were used, introduced, and or repurposed to fight against COVID-19. Furthermore, drug-likeness properties of the mentioned small heterocyclic frameworks (4a‒n) have been explored using in silico ADMET analyses. Interestingly, the molecular docking studies and ADMET-related data revealed that the novel series of furo[2,3-d]pyrimidines (4a‒n), especially 5-(3,4-methylendioxybenzoyl)-6-(cyclohexylamino)-1,3-dimethylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (4g) as hit one is potential COVID-19 drug candidate, can subject to further in vitro and in vivo studies. It is worthwhile to note that the protein-ligand-type molecular docking studies on the human body temperature-dependent MPro protein that surprisingly contains zincII (ZnII) ion between His41/Cys145 catalytic dyad in the active site, which undoubtedly can make new plans for designing novel SARS-CoV-2 MPro inhibitors, is performed for the first time in this paper, to the best of our knowledge.

Setomimycin as a potential molecule for COVID­19 target: in silico approach and in vitro validation.

COVID-19 pandemic caused by the SARS-CoV-2 virus has led to a worldwide crisis. In view of emerging variants time to time, there is a pressing need of effective COVID-19 therapeutics. Setomimycin, a rare tetrahydroanthracene antibiotic, remained unexplored for its therapeutic uses. Herein, we report our investigations on the potential of setomimycin as COVID-19 therapeutic. Pure setomimycin was isolated from Streptomyces sp. strain RA-WS2 from NW Himalayan region followed by establishing in silico as well as in vitro anti-SARS-CoV-2 property of the compound against SARS-CoV-2 main protease (Mpro). It was found that the compound targets Mpro enzyme with an IC50 value of 12.02 ± 0.046 µM. The molecular docking study revealed that the compound targets Glu166 residue of Mpro enzyme, hence preventing dimerization of SARS-CoV-2 Mpro monomer. Additionally, the compound also exhibited anti-inflammatory and anti-oxidant property, suggesting that setomimycin may be a viable option for application against COVID-19 infections.

In Silico Screening of Natural Flavonoids against 3-Chymotrypsin-like Protease of SARS-CoV-2 Using Machine Learning and Molecular Modeling.

The "Long-COVID syndrome" has posed significant challenges due to a lack of validated therapeutic options. We developed a novel multi-step virtual screening strategy to reliably identify inhibitors against 3-chymotrypsin-like protease of SARS-CoV-2 from abundant flavonoids, which represents a promising source of antiviral and immune-boosting nutrients. We identified 57 interacting residues as contributors to the protein-ligand binding pocket. Their energy interaction profiles constituted the input features for Machine Learning (ML) models. The consensus of 25 classifiers trained using various ML algorithms attained 93.9% accuracy and a 6.4% false-positive-rate. The consensus of 10 regression models for binding energy prediction also achieved a low root-mean-square error of 1.18 kcal/mol. We screened out 120 flavonoid hits first and retained 50 drug-like hits after predefined ADMET filtering to ensure bioavailability and safety profiles. Furthermore, molecular dynamics simulations prioritized nine bioactive flavonoids as promising anti-SARS-CoV-2 agents exhibiting both high structural stability (root-mean-square deviation < 5 Å for 218 ns) and low MM/PBSA binding free energy (<-6 kcal/mol). Among them, KB-2 (PubChem-CID, 14630497) and 9-O-Methylglyceofuran (PubChem-CID, 44257401) displayed excellent binding affinity and desirable pharmacokinetic capabilities. These compounds have great potential to serve as oral nutraceuticals with therapeutic and prophylactic properties as care strategies for patients with long-COVID syndrome.

Evaluating anti-coronavirus activity of some phosphoramides and their influencing inhibitory factors using molecular docking, DFT, QSAR, and NCI-RDG studies.

The recent prevalence of coronavirus disease in 2019 (COVID-19) has triggered widespread global health concerns.Antiviral drugs based on phosphoramides have significant inhibitory activity against the main protease (Mpro) of the virus and prevent transcription and viral replication. Hence, in order to design and introduce a group of inhibitors affecting the coronavirus, 35 phosphoramide compounds based on phospho-guanine and phospho-pyrazine derivatives were selected for molecular docking study. The results showed that most phosphoguanides containing the amino benzimidazole have a high interaction tendency with COVID-19. Among them, compound 19 was identified as the strongest inhibitor with the -9.570 kcal/mol binding energy whereas, the binding energy of Remdesivir is -6.75 kcal/mol. The quantitative structure-activity relationship (QSAR) results demonstrated that the number of aromatic rings, amide's nitrogens and their ability in π-staking, and hydrogen interactions with Mpro active sites are major factors contributing to the inhibitory activity of these compounds.Also, the NCI-RDG and DFT results were in good accordance with those of QSAR and molecular docking. The findings of this investigation can be underlying the synthesis of effective and efficient drugs against COVID-19.

Discovery of TCMs and derivatives against the main protease of SARS-CoV-2 via high throughput screening, ADMET analysis, and inhibition assay in vitro.

The rapidly evolving Coronavirus Disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide with thousands of deaths and infected cases. For the identification of effective treatments against this disease, the main protease (Mpro) of SARS­CoV­2 was found to be an attractive drug target, as it played a central role in viral replication and transcription. Here, we report the results of high-throughput molecular docking with 1,045,468 ligands' structures from 116 kinds of traditional Chinese medicine (TCM). Subsequently, 465 promising candidates were obtained, showing high binding affinities. The dynamic simulation, ADMET (absorption, distribution, metabolism, excretion and toxicity) and drug-likeness properties were further analyzed the screened docking results. Basing on these simulation results, 23 kinds of Chinese herbal extracts were employed to study their inhibitory activity for Mpro of SARS­CoV­2. Plants extracts from Forsythiae Fructus, Radix Puerariae, Radix astragali, Anemarrhenae Rhizoma showed acceptable inhibitory efficiencies, which were over 70%. The best candidate was Anemarrhenae Rhizoma, reaching 78.9%.

Identification of SARS-CoV-2 Main Protease Inhibitors from a Library of Minor Cannabinoids by Biochemical Inhibition Assay and Surface Plasmon Resonance Characterized Binding Affinity.

The replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its main protease (Mpro), which is a plausible therapeutic target for coronavirus disease 2019 (COVID-19). Although numerous in silico studies reported the potential inhibitory effects of natural products including cannabis and cannabinoids on SARS-CoV-2 Mpro, their anti-Mpro activities are not well validated by biological experimental data. Herein, a library of minor cannabinoids belonging to several chemotypes including tetrahydrocannabinols, cannabidiols, cannabigerols, cannabichromenes, cannabinodiols, cannabicyclols, cannabinols, and cannabitriols was evaluated for their anti-Mpro activity using a biochemical assay. Additionally, the binding affinities and molecular interactions between the active cannabinoids and the Mpro protein were studied by a biophysical technique (surface plasmon resonance; SPR) and molecular docking, respectively. Cannabinoids tetrahydrocannabutol and cannabigerolic acid were the most active Mpro inhibitors (IC50 = 3.62 and 14.40 µM, respectively) and cannabigerolic acid had a binding affinity KD=2.16×10-4 M). A preliminary structure and activity relationship study revealed that the anti-Mpro effects of cannabinoids were influenced by the decarboxylation of cannabinoids and the length of cannabinoids' alkyl side chain. Findings from the biochemical, biophysical, and computational assays support the growing evidence of cannabinoids' inhibitory effects on SARS-CoV-2 Mpro.

Comparative protein structure network analysis on 3CLpro from SARS-CoV-1 and SARS-CoV-2.

The main protease Mpro , 3CLpro is an important target from coronaviruses. In spite of having 96% sequence identity among Mpros from SARS-CoV-1 and SARS-CoV-2; the inhibitors used to block the activity of SARS-CoV-1 Mpro so far, were found to have differential inhibitory effect on Mpro of SARS-CoV-2. The possible reason could be due to the difference of few amino acids among the peptidases. Since, overall 3-D crystallographic structure of Mpro from SARS-CoV-1 and SARS-CoV-2 is quite similar and mapping a subtle structural variation is seemingly impossible. Hence, we have attempted to study a structural comparison of SARS-CoV-1 and SARS-CoV-2 Mpro in apo and inhibitor bound states using protein structure network (PSN) based approach at contacts level. The comparative PSNs analysis of apo Mpros from SARS-CoV-1 and SARS-CoV-2 uncovers small but significant local changes occurring near the active site region and distributed throughout the structure. Additionally, we have shown how inhibitor binding perturbs the PSG and the communication pathways in Mpros . Moreover, we have also investigated the network connectivity on the quaternary structure of Mpro and identified critical residue pairs for complex formation using three centrality measurement parameters along with the modularity analysis. Taken together, these results on the comparative PSN provide an insight into conformational changes that may be used as an additional guidance towards specific drug development.

Using Chou's 5-steps rule to study pharmacophore-based virtual screening of SARS-CoV-2 Mpro inhibitors.

Recently emerged SARS-CoV-2 is the cause of the ongoing outbreak of COVID-19. It is responsible for the deaths of millions of people and has caused global economic and social disruption. The numbers of COVID-19 cases are increasing exponentially across the world. Control of this pandemic disease is challenging because there is no effective drug or vaccine available against this virus and this situation demands an urgent need for the development of anti-SARS-CoV-2 potential medicines. In this regard, the main protease (Mpro) has emerged as an essential drug target as it plays a vital role in virus replication and transcription. In this research, we have identified two novel potent inhibitors of the Mpro (PubChem3408741 and PubChem4167619) from PubChem database by pharmacophore-based high-throughput virtual screening. The molecular docking, toxicity, and pharmacophore analysis indicate that these compounds may act as potential anti-viral candidates. The molecular dynamic simulation along with the binding free energy calculation by MMPBSA showed that these compounds bind to Mpro enzyme with high stability over 50 ns. Our results showed that two compounds: PubChem3408741 and PubChem4167619 had the binding free energy of - 94.02 kJ mol-1 and - 122.75 kJ mol-1, respectively, as compared to reference X77 (- 76.48 kJ mol-1). Based on our work's findings, we propose that these compounds can be considered as lead molecules for targeting Mpro enzyme and they can be potential SARS-CoV-2 inhibitors. These inhibitors could be tested in vitro and explored for effective drug development against COVID-19.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (Mpro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces Mpro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 Mpro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of Mpro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of Mpro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

An in-silico study on selected organosulfur compounds as potential drugs for SARS-CoV-2 infection via binding multiple drug targets.

The emerging paradigm shift from 'one molecule, one target, for one disease' towards 'multi-targeted small molecules' has paved an ingenious pathway in drug discovery in recent years. We extracted this idea for the investigation of drugs for COVID-19. Perceiving the importance of organosulfur compounds, seventy-six known organosulfur compounds were screened and studied for the interaction with multiple SARS-CoV-2 target proteins by molecular dynamics simulation. Lurasidone and its derivatives displayed substantial binding affinity against five proteins (Mpro, PLpro, Spro, helicase and RdRp). The pharmacokinetics, ADMET properties and target prediction studies performed in this work further potentiates the effectiveness against SARS-CoV-2.

COVID-19: In silico identification of potent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2.

The COVID-19 has been creating a global crisis, causing countless deaths and unbearable panic. Despite the progress made in the development of the vaccine, there is an urge need for the discovery of antivirals that may better work at different stages of SARS-CoV-2 reproduction. The main protease (Mpro) of the SARS-CoV-2 is a crucial therapeutic target due to its critical function in virus replication. The α-ketoamide derivatives represent an important class of inhibitors against the Mpro of the SARS-CoV. While there is 99% sequence similarity between SARS-CoV and SARS-CoV-2 main proteases, anti-SARS-CoV compounds may have a huge demonstration's prospect of their effectiveness against the SARS-CoV-2. In this study, we applied various computational approaches to investigate the inhibition potency of novel designed α-ketoamide-based compounds. In this regard, a set of 21 α-ketoamides was employed to construct a QSAR model, using the genetic algorithm-multiple linear regression (GA-MLR), as well as a pharmacophore fit model. Based on the GA-MLR model, 713 new designed molecules were reduced to 150 promising hits, which were later subject to the established pharmacophore fit model. Among the 150 compounds, the best selected compounds (3 hits) with greater pharmacophore fit score were further studied via molecular docking, molecular dynamic simulations along with the Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Our approach revealed that the three hit compounds could serve as potential inhibitors against the SARS-CoV-2 Mpro target.

Synthesis, crystal structure, computational study and anti-virus effect of mixed ligand copper (II) complex with ONS donor Schiff base and 1, 10-phenanthroline.

This work deals with the synthesis, crystal structure, computational study and antiviral potential of mixed ligand copper(II) complex [Cu(L)(phen)](1), (where, H2L = (Z)-N'-((E)-2-hydroxy-3,5-diiodobenzylidene)-N,N-dimethylcarbamohydrazonothioic acid, phen = 1,10-phenanthroline). The Schiff base ligand (H2L) is coordinated with Cu(II) ion in O, N, S-tridentate mode. The copper complex (1) crystallized in the monoclinic system of the space group P21/c with eight molecules in the unit cell and reveals a square pyramidal geometry. Furthermore, we also perform quantum chemical calculations to get insights into the structure-property relationship and functional properties of ligand (H2L) and its copper (II) complex [Cu(L)(phen)](1). Complex [Cu(L)(phen)](1) was also virtually designed in-silico evaluation by Swiss-ADME. Additionally, inspiring by recent developments to find a potential inhibitor for the COVID-19 virus, we have also performed molecular docking study of ligand and its copper complex (1) to see if our compounds shows an affinity for the main protease (Mpro) of COVID-19 spike protein (PDB ID: 7C8U). Interestingly, the results are found quite encouraging where the binding affinity and inhibition constant were found to be -7.14 kcal/mol and 5.82 µM for ligand (H2L) and -6.18 kcal/mol and 0.76 µM for complex [Cu(L)(phen)](1) with Mpro protein. This binding affinity is reasonably well as compared to recently known antiviral drugs. For instance, the binding affinity of ligand and complex was found to be better than docking results of chloroquine (-6.293 kcal/mol), hydroxychloroquine (-5.573 kcal/mol) and remdesivir (-6.352 kcal/mol) with Mpro protein. The present study may offer the technological solutions and potential inhibition to the COVID-19 virus in the ongoing and future challenges of the global community. In the framework of synthesis and characterization of mixed ligand copper (II) complex; the major conclusions can be drawn as follow.

COVID-19: Direct and Indirect Mechanisms of Statins.

The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-ß and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.

Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design.

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM-GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.